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Properties of antiepileptic drugs in the treatment of idiopathic generalized epilepsies.
Epilepsia 2005; 46 Suppl 9:140-8E

Abstract

Although valproate is considered to be the drug of first choice for the treatment of idiopathic generalized epilepsies (IGEs), other antiepileptic drugs (AEDs), both old (ethosuximide, clobazam, and clonazepam) and new (lamotrigine, levetiracetam, topiramate, and zonisamide) are also available. These AEDs do not appear to have a common mechanism of action in that both inhibitory gamma-aminobutyric acid (GABA; e.g., clobazam, clonazepam, and valproate) and excitatory glutamate (e.g., lamotrigine and topiramate) mechanisms are involved. Ethosuximide primarily acts by blocking T-type voltage-gated calcium channels in thalamic neurones while topiramate and zonisamide have multiple mechanisms of action. In contrast, levetiracetam is unique in that it may act via a specific binding site in the brain. In terms of their pharmacokinetic characteristics, all eight AEDs are rapidly absorbed after oral ingestion with peak blood concentration being achieved within 1-4 hours. Bioavailability is 100% with the exception clonazepam (90%) and topiramate (81-95%). Plasma protein binding is variable with valproate (90%), clobazam (85%) and clonazepam (86%) showing substantial binding, lamotrigine (55%) and zonisamide (50%) intermediate binding, and levetiracetam (0%), ethosuximide (0%) and topiramate (10%) being minimally bound. However, the binding by zonisamide is complicated by its binding to erythrocytes as well as albumin. All AEDs, with the exception of lamotrigine and levetiracetam, undergo elimination as a result of extensive metabolism by hepatic cytochrome P450 enzymes, which are highly amenable to induction and inhibition by other drugs and therefore susceptible to pharmacokinetic interactions. Lamotrigine metabolism is via hepatic glucuronidation, a process that is also susceptible to induction and inhibition by concurrent drugs. Levetiracetam is minimally metabolized (by hydrolysis in blood), is excreted predominantly unchanged in urine, and to date has not been associated with any clinically significant pharmacokinetic interactions. Using a semiquantitative pharmacokinetic rating system, based on 16 pharmacokinetic characteristics, a direct comparison between AEDs is possible. Thus valproic acid, regarded as the drug of first choice in the treatment of IGEs, rates lowest with respect to favorable pharmacokinetic characteristics, mostly because of its nonlinear pharmacokinetics, extensive hepatic metabolism, and its high propensity to interact both with other AEDs and non-AEDs. Levetiracetam rates highest with topiramate in second place.

Authors+Show Affiliations

Pharmacology and Therapeutics Unit, Department of Clinical and Experimental Epilepsy, Institute of Neurology, London, United Kingdom. P.Patsalos@ion.ucl.ac.uk

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

16302888

Citation

Patsalos, Philip N.. "Properties of Antiepileptic Drugs in the Treatment of Idiopathic Generalized Epilepsies." Epilepsia, vol. 46 Suppl 9, 2005, pp. 140-8.
Patsalos PN. Properties of antiepileptic drugs in the treatment of idiopathic generalized epilepsies. Epilepsia. 2005;46 Suppl 9:140-8.
Patsalos, P. N. (2005). Properties of antiepileptic drugs in the treatment of idiopathic generalized epilepsies. Epilepsia, 46 Suppl 9, pp. 140-8.
Patsalos PN. Properties of Antiepileptic Drugs in the Treatment of Idiopathic Generalized Epilepsies. Epilepsia. 2005;46 Suppl 9:140-8. PubMed PMID: 16302888.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Properties of antiepileptic drugs in the treatment of idiopathic generalized epilepsies. A1 - Patsalos,Philip N, PY - 2005/11/24/pubmed PY - 2005/12/13/medline PY - 2005/11/24/entrez SP - 140 EP - 8 JF - Epilepsia JO - Epilepsia VL - 46 Suppl 9 N2 - Although valproate is considered to be the drug of first choice for the treatment of idiopathic generalized epilepsies (IGEs), other antiepileptic drugs (AEDs), both old (ethosuximide, clobazam, and clonazepam) and new (lamotrigine, levetiracetam, topiramate, and zonisamide) are also available. These AEDs do not appear to have a common mechanism of action in that both inhibitory gamma-aminobutyric acid (GABA; e.g., clobazam, clonazepam, and valproate) and excitatory glutamate (e.g., lamotrigine and topiramate) mechanisms are involved. Ethosuximide primarily acts by blocking T-type voltage-gated calcium channels in thalamic neurones while topiramate and zonisamide have multiple mechanisms of action. In contrast, levetiracetam is unique in that it may act via a specific binding site in the brain. In terms of their pharmacokinetic characteristics, all eight AEDs are rapidly absorbed after oral ingestion with peak blood concentration being achieved within 1-4 hours. Bioavailability is 100% with the exception clonazepam (90%) and topiramate (81-95%). Plasma protein binding is variable with valproate (90%), clobazam (85%) and clonazepam (86%) showing substantial binding, lamotrigine (55%) and zonisamide (50%) intermediate binding, and levetiracetam (0%), ethosuximide (0%) and topiramate (10%) being minimally bound. However, the binding by zonisamide is complicated by its binding to erythrocytes as well as albumin. All AEDs, with the exception of lamotrigine and levetiracetam, undergo elimination as a result of extensive metabolism by hepatic cytochrome P450 enzymes, which are highly amenable to induction and inhibition by other drugs and therefore susceptible to pharmacokinetic interactions. Lamotrigine metabolism is via hepatic glucuronidation, a process that is also susceptible to induction and inhibition by concurrent drugs. Levetiracetam is minimally metabolized (by hydrolysis in blood), is excreted predominantly unchanged in urine, and to date has not been associated with any clinically significant pharmacokinetic interactions. Using a semiquantitative pharmacokinetic rating system, based on 16 pharmacokinetic characteristics, a direct comparison between AEDs is possible. Thus valproic acid, regarded as the drug of first choice in the treatment of IGEs, rates lowest with respect to favorable pharmacokinetic characteristics, mostly because of its nonlinear pharmacokinetics, extensive hepatic metabolism, and its high propensity to interact both with other AEDs and non-AEDs. Levetiracetam rates highest with topiramate in second place. SN - 0013-9580 UR - https://www.unboundmedicine.com/medline/citation/16302888/Properties_of_antiepileptic_drugs_in_the_treatment_of_idiopathic_generalized_epilepsies_ L2 - https://doi.org/10.1111/j.1528-1167.2005.00326.x DB - PRIME DP - Unbound Medicine ER -